-
Human Reproduction Update Jan 2023Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main... (Review)
Review
BACKGROUND
Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive health and causing tubal infertility, ectopic tubal pregnancy and premature delivery. Among male infertility factors, 13-15% of male infertility is related to infection. Defensins are cationic antibacterial and antiviral peptides, classified into α-defensins, β-defensins and θ-defensins. Humans only have α-defensins and β-defensins. Apart from their direct antimicrobial functions, defensins have an immunomodulatory function and are involved in many physiological processes. Studies have shown that defensins are widely distributed in the female reproductive tract (FRT) and male reproductive tract (MRT), playing a dual role of host defence and fertility protection. However, to our knowledge, the distribution, regulation and function of defensins in the reproductive tract and their relation to reproduction have not been reviewed.
OBJECTIVE AND RATIONALE
This review summarizes the expression, distribution and regulation of defensins in the reproductive tracts to reveal the updated research on the dual role of defensins in host defence and the protection of fertility.
SEARCH METHODS
A systematic search was conducted in PubMed using the related keywords through April 2022. Related data from original researches and reviews were integrated to comprehensively review the current findings and understanding of defensins in the human reproductive system. Meanwhile, female and male transcriptome data in the GEO database were screened to analyze defensins in the human reproductive tracts.
OUTCOMES
Two transcriptome databases from the GEO database (GSE7307 and GSE150852) combined with existing researches reveal the expression levels and role of the defensins in the reproductive tracts. In the FRT, a high expression level of α-defensin is found, and the expression levels of defensins in the vulva and vagina are higher than those in other organs. The expression of defensins in the endometrium varies with menstrual cycle stages and with microbial invasion. Defensins also participate in the local immune response to regulate the risk of spontaneous preterm birth. In the MRT, a high expression level of β-defensins is also found. It is mainly highly expressed in the epididymal caput and corpus, indicating that defensins play an important role in sperm maturation. The expression of defensins in the MRT varies with androgen levels, age and the status of microbial invasion. They protect the male reproductive system from bacterial infections by neutralizing lipopolysaccharide and downregulating pro-inflammatory cytokines. In addition, animal and clinical studies have shown that defensins play an important role in sperm maturation, motility and fertilization.
WIDER IMPLICATIONS
As a broad-spectrum antimicrobial peptide without drug resistance, defensin has great potential for developing new natural antimicrobial treatments for reproductive tract infections. However, increasing evidence has shown that defensins can not only inhibit microbial invasion but can also promote the invasion and adhesion of some microorganisms in certain biological environments, such as human immunodeficiency virus. Therefore, the safety of defensins as reproductive tract anti-infective drugs needs more in-depth research. In addition, the modulatory role of defensins in fertility requires more in-depth research since the current conclusions are based on small-size samples. At present, scientists have made many attempts at the clinical transformation of defensins. However, defensins have problems such as poor stability, low bioavailability and difficulties in their synthesis. Therefore, the production of safe, effective and low-cost drugs remains a challenge.
Topics: Infant, Newborn; Pregnancy; Animals; Humans; Male; Female; beta-Defensins; alpha-Defensins; Reproductive Health; Infertility, Female; Semen; Premature Birth; Defensins; Infertility, Male; Anti-Infective Agents
PubMed: 36130055
DOI: 10.1093/humupd/dmac032 -
Signal Transduction and Targeted Therapy Aug 2023As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their... (Review)
Review
As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.
Topics: Animals; Humans; Paneth Cells; Inflammatory Bowel Diseases; Defensins
PubMed: 37574471
DOI: 10.1038/s41392-023-01553-x -
Immunity Sep 2022Healthy skin maintains a diverse microbiome and a potent immune system to fight off infections. Here, we discovered that the epithelial-cell-derived antimicrobial...
Healthy skin maintains a diverse microbiome and a potent immune system to fight off infections. Here, we discovered that the epithelial-cell-derived antimicrobial peptides defensins activated orphan G-protein-coupled receptors (GPCRs) Mrgpra2a/b on neutrophils. This signaling axis was required for effective neutrophil-mediated skin immunity and microbiome homeostasis. We generated mutant mouse lines lacking the entire Defensin (Def) gene cluster in keratinocytes or Mrgpra2a/b. Def and Mrgpra2 mutant animals both exhibited skin dysbiosis, with reduced microbial diversity and expansion of Staphylococcus species. Defensins and Mrgpra2 were critical for combating S. aureus infections and the formation of neutrophil abscesses, a hallmark of antibacterial immunity. Activation of Mrgpra2 by defensin triggered neutrophil release of IL-1β and CXCL2 which are vital for proper amplification and propagation of the antibacterial immune response. This study demonstrated the importance of epithelial-neutrophil signaling via the defensin-Mrgpra2 axis in maintaining healthy skin ecology and promoting antibacterial host defense.
Topics: Animals; Mice; Anti-Bacterial Agents; Bacterial Infections; Carrier Proteins; Defensins; Dysbiosis; Keratinocytes; Neutrophils; Receptors, G-Protein-Coupled; Staphylococcus aureus
PubMed: 35882236
DOI: 10.1016/j.immuni.2022.06.021 -
Molecules (Basel, Switzerland) Jul 2022Antimicrobial resistance requires urgent efforts towards the discovery of active antimicrobials, and the development of strategies to sustainably produce them. Defensin...
Antimicrobial resistance requires urgent efforts towards the discovery of active antimicrobials, and the development of strategies to sustainably produce them. Defensin and defensin-like antimicrobial peptides (AMPs) are increasingly gaining pharmacological interest because of their potency against pathogens. In this study, we expressed two AMPs: defensin-d2 derived from spinach, and defensin-like actifensin from . Recombinant pTXB1 plasmids carrying the target genes encoding defensin-d2 and actifensin were generated by the MEGAWHOP cloning strategy. Each AMP was first expressed as a fusion protein in , purified by affinity chromatography, and was thereafter assayed for antimicrobial activity against multidrug-resistant (MDR) pathogens. Approximately 985 µg/mL and 2895 µg/mL of recombinant defensin-d2 and actifensin, respectively, were recovered with high purity. An analysis by MALDI-TOF MS showed distinct peaks corresponding to molecular weights of approximately 4.1 kDa for actifensin and 5.8 kDa for defensin-d2. An in vitro antimicrobial assay showed that MDR and were inhibited at minimum concentrations of 7.5 µg/mL and 23 µg/mL for recombinant defensin-d2 and actifensin, respectively. The inhibitory kinetics of the peptides revealed cidal activity within 4 h of the contact time. Furthermore, both peptides exhibited an antagonistic interaction, which could be attributed to their affinities for similar ligands, as deduced by peptide-ligand profiling. Moreover, both peptides inhibited biofilm formation, and they exhibited no resistance potential and low hemolytic activity. The peptides also possess the ability to permeate and disrupt the cell membranes of MDR and . Therefore, recombinant actifensin and defensin-d2 exhibit broad-spectrum antimicrobial activity and have the potential to be used as therapy against MDR pathogens.
Topics: Anti-Bacterial Agents; Anti-Infective Agents; Candida albicans; Defensins; Drug Resistance, Bacterial; Escherichia coli; Microbial Sensitivity Tests; Peptides; Pseudomonas aeruginosa; Recombinant Proteins
PubMed: 35889198
DOI: 10.3390/molecules27144325 -
Current Pharmaceutical Design 2013Antimicrobial peptides (AMPs) are important components of innate immunity. They are often expressed in response to colonic inflammation and infection. Over the last... (Review)
Review
Antimicrobial peptides (AMPs) are important components of innate immunity. They are often expressed in response to colonic inflammation and infection. Over the last several years, the roles of several antimicrobial peptides have been explored. Gene expression of many AMPs (beta defensin HBD2-4 and cathelicidin) is induced in response to invasion of gut microbes into the mucosal barrier. Some AMPs are expressed in a constitutive manner (alpha defensin HD 5-6 and beta defensin HBD1), while others (defensin and bactericidal/ permeability increasing protein BPI) are particularly associated with Inflammatory Bowel Disease (IBD) due to altered defensin expression or development of autoantibodies against Bactericidal/permeability increasing protein (BPI). Various AMPs have different spectrum and strength of antimicrobial effects. Some may play important roles in modulating the colitis (cathelicidin) while others (lactoferrin, hepcidin) may represent biomarkers of disease activity. The use of AMPs for therapeutic purposes is still at an early stage of development. A few natural AMPs were shown to be able to modulate colitis when delivered intravenously or intracolonically (cathelicidin, elafin and SLPI) in mouse colitis models. New AMPs (synthetic or artificial non-human peptides) are being developed and may represent new therapeutic approaches against colitis. This review discusses the latest research developments in the AMP field with emphasis in innate immunity and pathophysiology of colitis.
Topics: Animals; Antimicrobial Cationic Peptides; Colitis; Colon; Disease Models, Animal; Drug Design; Gene Expression Regulation; Humans; Ileum; Inflammation; Inflammatory Bowel Diseases; Mice; alpha-Defensins; beta-Defensins
PubMed: 22950497
DOI: 10.2174/13816128130108 -
Journal of Leukocyte Biology May 2016Both α- and β-defensins have anti-human immunodeficiency virus activity. These defensins achieve human immunodeficiency virus inhibition through a variety of... (Review)
Review
Both α- and β-defensins have anti-human immunodeficiency virus activity. These defensins achieve human immunodeficiency virus inhibition through a variety of mechanisms, including direct binding with virions, binding to and modulation of host cell-surface receptors with disruption of intracellular signaling, and functioning as chemokines or cytokines to augment and alter adaptive immune responses. Polymorphisms in the defensin genes have been associated with susceptibility to human immunodeficiency virus infection and disease progression. However, the roles that these defensins and their genetic polymorphisms have in influencing human immunodeficiency virus/acquired immunodeficiency syndrome outcomes are not straightforward and, at times, appear contradictory. Differences in populations, study designs, and techniques for genotyping defensin gene polymorphisms may have contributed to this lack of clarity. In addition, a comprehensive approach, where both subfamilies of defensins and their all-inclusive genetic polymorphism profiles are analyzed, is lacking. Such an approach may reveal whether the human immunodeficiency virus inhibitory activities of α- and β-defensins are based on parallel or divergent mechanisms and may provide further insights into how the genetic predisposition for susceptibility or resistance to human immunodeficiency virus/acquired immunodeficiency syndrome is orchestrated between these molecules.
Topics: Acquired Immunodeficiency Syndrome; DNA Copy Number Variations; Defensins; Genetic Variation; Genome, Human; Humans; Polymorphism, Single Nucleotide
PubMed: 26957215
DOI: 10.1189/jlb.6RU1215-560R -
International Journal of Molecular... Mar 2023Defensins have long been considered as merely antimicrobial peptides. Throughout the years, more immune-related functions have been discovered for both the α-defensin... (Review)
Review
Defensins have long been considered as merely antimicrobial peptides. Throughout the years, more immune-related functions have been discovered for both the α-defensin and β-defensin subfamily. This review provides insights into the role of defensins in tumor immunity. Since defensins are present and differentially expressed in certain cancer types, researchers started to unravel their role in the tumor microenvironment. The human neutrophil peptides have been demonstrated to be directly oncolytic by permealizing the cell membrane. Further, defensins can inflict DNA damage and induce apoptosis of tumor cells. In the tumor microenvironment, defensins can act as chemoattractants for subsets of immune cells, such as T cells, immature dendritic cells, monocytes and mast cells. Additionally, by activating the targeted leukocytes, defensins generate pro-inflammatory signals. Moreover, immuno-adjuvant effects have been reported in a variety of models. Therefore, the action of defensins reaches beyond their direct antimicrobial effect, i.e., the lysis of microbes invading the mucosal surfaces. By causing an increase in pro-inflammatory signaling events, cell lysis (generating antigens) and attraction and activation of antigen presenting cells, defensins could have a relevant role in activating the adaptive immune system and generating anti-tumor immunity, and could thus contribute to the success of immune therapy.
Topics: Humans; beta-Defensins; T-Lymphocytes; alpha-Defensins; Monocytes; Biology; Defensins
PubMed: 36982340
DOI: 10.3390/ijms24065268 -
Sheng Li Xue Bao : [Acta Physiologica... Jun 2015There are at least three conserved protein folds shared by ion channel-targeted neurotoxins and antimicrobial defensins, including cysteine-stabilized α-helix and... (Review)
Review
There are at least three conserved protein folds shared by ion channel-targeted neurotoxins and antimicrobial defensins, including cysteine-stabilized α-helix and β-sheet fold (CSαβ), inhibitor cystine knot fold (ICK) and β-defensin fold (BDF). Based on a combined data of sequences, structures and functions, it has been proposed that these neurotoxins could originate from related ancient antimicrobial defensins by neofunctionalization. This provides an ideal system to study how a novel function emerged from a conserved structural scaffold during evolution. The elucidation of functional novelty of proteins not only has great significance in evolutionary biology but also will be helpful in guiding rational molecular design. This review describes recent progresses in origin of neurotoxins, focusing on the three conserved protein scaffolds.
Topics: Defensins; Evolution, Molecular; Neurotoxins; Protein Structure, Secondary
PubMed: 26109296
DOI: No ID Found -
International Journal of Molecular... Jul 2020Plant defensins form a family of proteins with a broad spectrum of protective activities against fungi, bacteria, and insects. Furthermore, some plant defensins have... (Review)
Review
Plant defensins form a family of proteins with a broad spectrum of protective activities against fungi, bacteria, and insects. Furthermore, some plant defensins have revealed anticancer activity. In general, plant defensins are non-toxic to plant and mammalian cells, and interest in using them for biotechnological and medicinal purposes is growing. Recent studies provided significant insights into the mechanisms of action of plant defensins. In this review, we focus on structural and dynamics aspects and discuss structure-dynamics-function relations of plant defensins.
Topics: Antineoplastic Agents, Phytogenic; Defensins; Humans; Models, Molecular; Plant Proteins; Plants; Structure-Activity Relationship
PubMed: 32722628
DOI: 10.3390/ijms21155307 -
Biomolecules Jul 2020The grass family (Poaceae) is one of the largest families of flowering plants, growing in all climatic zones of all continents, which includes species of exceptional... (Review)
Review
The grass family (Poaceae) is one of the largest families of flowering plants, growing in all climatic zones of all continents, which includes species of exceptional economic importance. The high adaptability of grasses to adverse environmental factors implies the existence of efficient resistance mechanisms that involve the production of antimicrobial peptides (AMPs). Of plant AMPs, defensins represent one of the largest and best-studied families. Although wheat and barley seed γ-thionins were the first defensins isolated from plants, the functional characterization of grass defensins is still in its infancy. In this review, we summarize the current knowledge of the characterized defensins from cultivated and selected wild-growing grasses. For each species, isolation of defensins or production by heterologous expression, peptide structure, biological activity, and structure-function relationship are described, along with the gene expression data. We also provide our results on in silico mining of defensin-like sequences in the genomes of all described grass species and discuss their potential functions. The data presented will form the basis for elucidation of the mode of action of grass defensins and high adaptability of grasses to environmental stress and will provide novel potent molecules for practical use in medicine and agriculture.
Topics: Defensins; Disease Resistance; Gene Expression Regulation, Plant; Models, Molecular; Plant Proteins; Poaceae; Protein Conformation; Structure-Activity Relationship
PubMed: 32664422
DOI: 10.3390/biom10071029